Field of the Invention
The present invention relates to the field of therapy for patients who have extravasation of blood internally, due to exposure to lethal or sub-lethal doses of radiation and other causes, with special attention to the reduction of the damage caused by the presence of break-down products from blood cells in the extravascular site.
The disclosed therapy comprises oral, intramuscular, subcutaneous, intraperitoneal and intravenous administration of agents that can bind or mitigate the effects of the break-down products of blood cells that have leaked into the extravascular space.
Description of the Prior Art
Exposure to massive doses of ionizing radiation, such as after a dirty-bomb or atomic-bomb explosion, or a nuclear-reactor or medical radiation accident, —whether the dose is definitely lethal (or sublethal if the patient has no co-morbidity)—can lead to major morbidity and/or mortality. If the victim survives the direct effect of the bomb blast, he still may suffer from damages to the nervous, digestive, pulmonary, hematopoietic and other vital systems. Published articles have revealed that transfusion of blood components, e.g. red blood cells and platelets can decrease the morbidity and mortality among irradiated patients. There is however, little attention paid to the effect of blood cells, e.g. red cells and white cells, which have leaked into the extravascular space which can cause the body to react in ways detrimental to the healing process needed to recover from the effects of irradiation.
One group of patients is particularly susceptible to the ill effects of suboptimal concentrations of red blood cells, white blood cells and platelets in vivo after exposure to irradiation, burn and chemotherapy. These are patients who are on anti-platelet treatment or anti-coagulation treatment for a variety of reasons. They become anemic and thrombocytopenic because they have excessive internal bleeding leading to increased morbidity and mortality compared to patients who are not on such anti-platelet or anti-coagulation treatments. These are the same patients who will have an excessive load of blood cells in the extravascular compartments, which will break down and cause inflammatory responses which will overwhelm the body's healing responses.
Various methods have been employed to treat radiation sickness, all of them not focused on dealing with the presence of break-down products in the extravascular compartment. For example: (1) Neumune, an androstenediol, had been used by the US Armed Forces Radiobiology Research Institute under joint development with Hollis-Eden Pharmaceuticals; (2) A Chinese herbal medicine called Cordyceps sinensis had been used to try to protect the bone marrow and digestion systems of mice after whole body irradiation; (3) Bisphosphonate compounds had also been tried; (4) U.S. Pat. No. 6,916,795 disclosed an “energy-protective composition” comprising adenosine phosphates; (5) Garnett and Remo disclosed at the International Symposium on Application of Enzymes in Chemical and Biological Defense, Plenary Session Abstract, May 2001 that “DNA Reductase” had some “Opportunist Clinical Activity Against Radiation Sickness”; and (6) U.S. Pat. No. 6,262,019 disclosed a composition called MAXGXL which contains glytathione. All of the above are soluble enzymes, steroids or small molecules.
Of particular interest is the discussion listed under: http://nextbigfuture.com/2009/07/radiation-sickness-cures-and-anti.html
It discussed:
(1) the effect of a small-molecule inhibitor to the p53-mediated apoptosis. A single shot of this drug, called CBLB502, at less than 1% of the maximum dose resulted in an 87% survival rate of mice exposed to an otherwise lethal dose of 13 Gray of radiation. By comparison, even at the maximum dose of the second-best chemical, called amifostine, only 54% of similarly irradiated mice survived.
(2) The work done at the Boston University School of Medicine on new compounds called the “EUK-400 series” which may be taken orally.
(3) DARPA funded work done at the Rice University called “Nanovector Trojan Horses, NTH.” These carbon nanotube-based drugs may scavenge free radicals and mitigate the effects of ionizing radiation. As disclosed by the authors, these compounds aim at the mitigation of the free radicals generated directly by the ionizing radiation and not at the breakdown products of blood cells, or caused by the blood cells, in the muscles, the tissues surrounding the nerves, the intestine, and other vital organs.
All of the above treatments employ mechanisms very different from the present invention. While some of the above mentioned treatments may result in improved survival of irradiated patients, it is not clear if the survivors will have other long-term medical problems caused by the irradiation or by the treatment. Therefore there is need for a new treatment that will improve survival, yet with less or no long-term medical problems among the survivors, caused either by the radiation or by the side-effects of the treatment.
Yen has disclosed a novel product useful to replace natural platelets, which can decrease the escape of blood cells from the intravascular system. The disclosures include: (a) the U.S. provisional patent application filed on Sep. 10, 2011, application No. 61/573,630, entitled “Submicron particles to decrease need for transfusion”; (b) the U.S. provisional patent application filed on Oct. 14, 2011, application No. 61/627,623, entitled “Submicron particles to decrease need for transfusion in some patients”; (c) the U.S. non-provisional patent application filed on Sep. 6, 2012, application Ser. No. 13/604,770 entitled “Submicron particles to decrease transfusion.” The entire disclosures of these prior applications are incorporated herein by reference. However, the disclosed invention deals with decreasing the leakiness of blood vessels and not with a therapy to deal with the removal of blood cells already leaked into the extravascular compartments or the mitigation of the effect of leaked blood cells, including red cells, white cells, platelets and plasma.
The break-down products include and not limited to: (a) cell membrane, which typically contains lipids that would provoke inflammatory responses; (b) enzymes; (c) nucleic acids (e.g. DNA and RNA from the white cells); but more importantly (d) hemoglobin and its further break-down products of (e) heme, (f) other iron species, (g) other globin molecules. Hemoglobin molecules outside the confinement of a red cell membrane is highly toxic to the body. It is well known that hemoglobin molecules can bind nitric oxide and other molecules which are vital in the maintenance of vasodilation. That is why when hemoglobin solutions (instead of red cells) are transfused in an attempt to resuscitate patients who have suffered massive blood loss, the result is always vasoconstriction and hypertension, leading to even less oxygen being delivered to the hypoxic tissues, which can actually accelerate death. Few studies in the literature have suggested that cellular break-down products can have a major impact on the survival of patients after a massive dose of irradiation. Therefore the approach of using drugs and other agents to facilitate the removal of the break-down products, or to mitigate their effects in the extravascular compartment is a novel and non-obvious invention.
In this application the term “improved survival” or “to improve survival” can mean (1) a prolong survival time, e.g. if 100% of the irradiated subjects will die before day-30 without treatment, a treatment will be considered effective in prolonging life if it takes longer than 30 days (e.g. a year) before 100% of a similarly irradiated group dies (possibly from other problems); (2) an increase in the survival rate at a fixed time (e.g. 30-day survival rate, or 90-day survival rate) after irradiation. Also the irradiation dose can be maximally lethal, leading to 100% of the irradiated subjects dying if untreated; or minimally lethal, having only, e.g. 5% of the irradiated subjects dying—both will be called “a lethal dose of irradiation.”
It is expected that augmentation of the effects of the present invention is possible, by the concomitant use of additional therapies, e.g. (a) by decreasing blood loss from the intravascular compartment, (b) by increasing oxygen delivery through transfusion of red cells and platelets, (c) by the use of bone marrow stimulating molecules so that the body can generate new red cells and new platelets faster, (d) by additional supportive therapy.
However, it would be most preferable that the new method of treatment disclosed here will be able to improve survival all by itself without the use of any blood transfusion or the use of any prior-art treatment for irradiated patients.
Indeed the administration of the present invention is expected to decrease the need for other therapy which had been used or attempted to be used to improve the morbidity and mortality of patients, before and after exposure to irradiation, e.g. the transfusion of blood components to these patients.
The term “blood component” in this invention can mean any protein and non-protein component extracted from blood, or a product manufactured in vitro as a molecule or as a recombinant product based on the gene or genes known to code for the naturally-made blood component. It can include cellular and non-cellular components of blood.
Examples in this application include patients exposed to radiation. It is to be understood that the beneficial effects of the present invention is not limited to irradiated patients, but will include all patients who suffer from leaky endothelium, resulting in blood cells escaping into the extravascular compartment. Examples will also include people exposed to thermal burns (external and internal), radiation burns, viral infections that cause bleeding, or people suffering from thrombocytopenia due to cancer, chemotherapy, and all kinds of procedures requiring transfusion of different kinds of blood cells to increase cell counts, such as patients who are septic or undergoing disseminated intravascular coagulation (DIC), thrombotic or hemorrhagic episodes, idiopathic (or immunological) thrombocytopenic purpura (ITP) or surgical patients.
Abkowitz et al disclosed a list of heme-binding agents in U.S. Pat. No. 8,119,773 B2. However, the authors used the heme-binding agents to facilitate heme-iron export from intact cells. There was no teaching on using heme-binding agents for the resuscitation of patients who have cell break-down products in the extravascular compartment.
The various compositions of the red cell membrane which need to be removed when present in the extravascular compartment can be found in: http://medtextfree.wordpress.com/2011/December/26/chapter-27-the-red-cell-membrane/.
We expect macrophages are involved in the clean-up of extravascular hemoglobin and extravascular membrane material. Both classically-activated macrophages (with Th1-like phenotype) and the alternatively-activated macrophages (with Th2-like phenotype) may be involved. The process may be different from what happens in the healthy body. In the healthy body, old erythrocytes are routinely phagocytized by macrophages in the spleen, liver and bone marrow, but the process does not leak free hemoglobin to the extracellular medium because the whole erythrocyte is degraded within the macrophage.
Part of the information disclosed in this application was filed with the USPTO as a commonly owned U.S. provisional application, No. 61/281,466 (“Submicron Particles for the Treatment of Radiation Damage in Patients”) and as a commonly owned U.S. non-provisional application, Ser. No. 12/927,543 filed on Nov. 16, 2010 with the same title. The entire disclosures of these prior applications are incorporated herein by reference.
Examples of Anti-Platelet and Anti-Coagulation Medication and Molecules
There are many anti-platelet products on the market. The following list provides only a sample of some of the known medications in the field:
1. ADP-receptor inhibitors: e.g. Cangrelor, Clopidogrel, Elinogrel, Prasugrel, Ticagrelor, Ticlopidine;
2. Aspirin;
3. GpIIb/IIIa inhibitors: e.g. abciximab, Eptifibatide, Tirofiban, and antibodies such as anti-CD41; and
4. Other candidates: e.g. Aloxiprin, Carbasalate, Cilostazol, Cloricromen, Clorindione, Dipyridamole, Ditazole, Indobufen, Picotamide, Ramatroban, Terbogrel, Terutroban, Trifusal.
Common anti-coagulation medications that thin blood by having mechanisms against coagulation factors include: heparin, warfarin, enoxaparin. Others inhibitors include direct thrombin-inhibitors (e.g. argatroban, lepirudin, bivalirudin, dabigatran, ximelagatran.) Still others inhibit factor Xa, e.g. Fondaparinux, Idraparinux, Rivaroxabin, Apixaban.
Examples of Agents that can Bind Heme and Other Break-Down Material from Blood Cells
List of agents that bind to or mitigate the harmful effects of heme (a metalloporphyrin) include the following:
I. Proteins mentioned in ““The Influence of heme-binding proteins in heme-catalyzed ozidations”” by Vincent S H et al., Arch Biochem Biophys. 1988, September; 265(2):539-50” include: Hemopexin, Human albumin, Glutathione S-transferases, Liver Fatty acid-binding proteins
II. Examples of antimalaria agents mentioned in ““Characterization of noncovalent complexes of antimalarial agents etc”” by Pashynska V A et al., J Am Soc Mass Spectrom. 2004, August; 15(8):1181-90”: Quinine, Artemisinin, Dihydroartemisinin, Alpha- and Beta-artemether, Beta-arteether
III. List of Heme-bind agents mentioned in ““Compositions and Methods for Facilitating Heme-Iron Export from Cells”” by Abkowitz et al., U.S. Pat. No. 8,119,773 B2, Feb. 21, 2012” include: Hemopexin, Synthetic heme binders, Bacterial Hemophores, Heme-binding protein 23 (HBP23; Peroxiredoxin 1, or Prx 1), Adrenal Inner Zone Antigen (IZA1), Rhodnius Heme-binding Protein (RHBP), NADPH-dependent Methemoglobin Reductase, Histidine-rich Protein 2 (HRP-2), Damage Resistance Protein 1 (Dap1p), HupA, Periplasmic Lipoprotein (HpbA), ShuT, PhuS, HemS, Bacterial Heme-binding Protei, Heme-binding agent with a heme-binding site having two histidines that are 43-52 amino acids apart and hydrophobic amino acids lining a heme binding pocket
IV. Chelators (Common or Synthetic)
Common chelators include citrate; desferrioxamine; 2,2′-bipyridine; nitrolotriacetic acid; 2,3-dimercapto-1-propanol (BAL); edathamil calcium disodium (CaEDTA); EDTA; d-penicillamine; 1,10-phenanthroline; bathophenanthroline sulfonate; N,N′-ethylenebis(o-hydroxyphenylglycine); 2,3-dihydroxybenzoic acid; catechol; tropolone; N,N′-bis(2,3-dihydroxybenzoyl)-1,6-diaminohexane.
Synthetic chelating agents include derivatives of pyridoxal or 2-hydroxybenzaldehyde and isonicotinic acid hydrazide or benzhydrazide, e.g. pyridoxal isonicotinoyl hydrazone, pyridoxal benzoyl hydrazone, 2-hydroxybenzal isonicotinoyl hydrazone, 2-hydroxybenzal benzoyl hydrazone, pyridoxal-valine Schiff base, pyridoxal.
V. Antioxidants (Reducing agents) include: Ascorbic acid, Thiols, Polyphenols, Glutathione, Lipoic Acid, Uric Acid, Carotenes, Alpha-Tocopherol, Ubiquinol.